Piperacillin

Uses

This is used for the treatment of the following systemic and/or local bacterial infections:

• Nosocomial pneumonia (moderate to severe)
• Community-acquired pneumonia (moderate severity only)
• Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous
• Abscesses and ischemic/diabetic foot infections
• Postpartum endometritis or pelvic inflammatory disease
• Appendicitis (complicated by rupture or abscess) and peritonitis
• Management of neutropenic patients (adults, adolescents and children) with fever suspected to be due to bacterial infections.

Piperacillin is also used to associated treatment for these conditions: Animal bite, Complicated Appendicitis, Pelvic Inflammatory Disease (PID), Peritonitis, Postpartum Endometritis, Surgical Site Infections, Moderate Bacterial Infections, Moderate Community acquired pneumonia, Moderate Nosocomial pneumonia, Severe Bacterial Infections, Severe Nosocomial pneumonia, Uncomplicated skin and subcutaneous tissue bacterial infectionsAnimal bite, Cellulitis, Complicated Appendicitis, Cutaneous Abscess, Diabetic Foot Ulcers (DFU), Pelvic Inflammatory Disease (PID), Peritonitis, Pneumonia, Hospital-Acquired, Postpartum Endometritis, Surgical Site Infections, Ventilator-Associated Pneumonia (VAP), Complicated Bacterial Urinary Tract Infections, Complicated Pyelonephritis, Complicated intra-abdominal bacterial infections, Moderate Bacterial Infections, Moderate Community acquired pneumonia, Moderate Nosocomial pneumonia, Severe Bacterial Infections, Severe Nosocomial pneumonia, Uncomplicated skin and subcutaneous tissue bacterial infections

How Piperacillin works

By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, Piperacillin inhibits the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins; it is possible that Piperacillin interferes with an autolysin inhibitor.

Tazobactam broadens the spectrum of piperacillin and ceftolozane by making them effective against organisms that express beta-lactamase and would normally degrade them. This occurs through the irreversible inhibition of beta-lactamase enzymes. In addition, tazobactam may bind covalently to plasmid-mediated and chromosome-mediated beta-lactamase enzymes. Tazobactam is predominantly effective against the OHIO-1, SHV-1, and TEM groups of beta-lactamases, but may also inhibit other beta-lactamases.

Tazobactam shows little antibacterial activity by itself, and for this reason, is generally not administered alone.

Dosage

Piperacillin dosage

Adults and children over 12 years: Piperacillin & Tazobactam may be given by slow intravenous infusion (over 20-30 minutes). The usual dosage for adults and children over 12 years is Piperacillin 4 gm and Tazobactam 0.5 gm IV infusion given every eight hours. The total daily dose of Piperacillin & Tazobactam depends on the severity and localization of the infection and can vary from 2.25 gm to 4.50 gm administered every six or eight hours. Inneutropenia the recommended dose is Piperacillin 4 gm and Tazobactam 0.5 gm given every six hours in combination with an aminoglycoside.

For children weighing less than 40 kg:The dose should be adjusted to 90 mg/kg administered every six hours, in combination with an aminoglycoside, not exceeding 4.5 gm every six hours.

Children under 2 years: Piperacillin & Tazobactam is not recommended for use in children below 2 years old due to insufficient data on safety.

Duration of Therapy: The duration of therapy should be guided by the severity of the infection and the patient's clinical and bacteriological progress. In acute infections, treatment with Piperacillin & Tazobactam should be continued for 48 hours beyond the resolution of clinical symptoms or the fever.

Reconstitute initially (2.25 g in 10 mL, 4.5 g in 20 mL) with water for inj, glucose 5% or NaCl 0.9%, then further dilute to 50-150 mL with compatible infusion soln.

Side Effects

Nausea, vomiting, diarrhoea; less commonly stomatitis, dyspepsia, constipation, jaundice, hypotension, headache, insomnia, and injection-site reactions; rarely abdominal pain, hepatitis, oedema, fatigue, and eosinophilia; very rarely hypoglycemia, hypokalaemia, pancytopenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis

Toxicity

Overdose

Post-marketing reports have been made of overdose cases with piperacillin/tazobactam. Nausea, vomiting, and diarrhea are frequent manifestations of an overdose. Neuromuscular excitability or seizures may also occur with high intravenous doses or renal failure. There is no specific antidote. Provide supportive measures in case of an overdose. Anticonvulsive agents may be indicated when neuromuscular excitability or seizures occur. If anaphylaxis occurs, traditional measures should be taken to manage hypersensitivity (for example, adrenaline, antihistamines, corticosteroids, and oxygen/airway maintenance). Similar measures should be taken after a ceftolozane-tazobactam overdose. Hemodialysis can be used to remove the drug from the circulation .

A note on nephrotoxicity

Cases of life-threatening nephrotoxicity have been seen in critically ill patients receiving piperacillin-tazobactam. Alternative therapy and/or renal monitoring should be considered in critically ill patients.

Carcinogenesis/Mutagenesis

Tazobactam tested negative for genotoxic effects in the Ames assay, an after in vitro chromosomal aberration and point mutation assay in the Chinese hamster, an various other assays.

Use in pregnancy

Tazobactam has been found cross the placenta in rats. No data on human studies are available, however, rat studies have shown no teratogenetic effects at doses 6-14 times the equivalent maximum recommended human dose.

Use in lactation

There are no data on the presence of tazobactam in human breastmilk. No data are currently available on the effects of tazobactam on the infant, or how it affects milk production. Use clinical judgement and consider the maternal need for the drug and the benefits of breastfeeding the infant before administration during lactation. Small concentrations of piperacillin-tazobactam have been found in the breastmilk and can lead to hypersensitivity in a breastfeeding infant. In some cases, breastfeeding may have to be discontinued temporarily.

Precaution

Patient with cystic fibrosis, history of seizure disorder. Renal impairment. Children. Pregnancy and lactation.

Interaction

Interaction with Probenecid: Concurrent administration of Probenecid and Piperacillin/Tazobactam produced a longer half-life and lower renal clearance for both Piperacillin and Tazobactam. However, peak plasma concentrations of either drug are unaffected.

Interaction with anticoagulants: During simultaneous administration of heparin, oral anticoagulants and other drugs which may affect the blood coagulation system including thrombocyte function, appropriate coagulation tests should be performed more frequently and monitored regularly.

Interaction with vecuronium: Piperacillin when used concomitantly with Vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non polarizing muscle relaxants could be prolonged in the presence of Piperacillin. This should be taken into account when Piperacillin/Tazobactam is used perioperatively.

Interaction with methotrexate: Piperacillin may reduce the excretion of methotrexate. Serum levels of methotrexate should be monitored in patients on methotrexate therapy

Volume of Distribution

• 101 mL/kg [intravenous administration of 50 mg/kg (5-minute infusion) in neonates]

18.2 L when given with piperacillin

13.5-18.2 L when given with ceftolozane

Piperacillin-tazobactam is widely distributed in body tissues and fluids. These may include but are not limited to the intestine, gallbladder, lung, female reproductive organs, and the bile. Meningeal distribution of piperacillin-tazobactam increases with inflammation, but is otherwise low.

Elimination Route

Not absorbed following oral administration.

Tazobactam is coadministered with piperacillin or ceftolozane, pharmacokinetic information will be provided for these combinations.

Piperacillin-tazobactam

Peak plasma concentrations occur immediately after the completion of intravenous infusion. Following several doses of piperacillin-tazobactam infusions every 6 hours, peak concentrations were similar to those that were measured after the initial dose.

Ceftolozane-piperacillin

AUC: 24.4-25 mcg•h/mL

Peak concentrations are reached on day 1 after the first dose and range from 18 to 18.4 mcg/mL.

Half Life

36-72 minutes

Piperacillin-tazobactam

After a single dose in healthy volunteers, the plasma half-life of piperacillin and tazobactam was in the range of 0.7 to 1.2 hours.

Ceftolozane-tazobactam

0.91-1.03 hours

Clearance

• 32 - 41 mL/min/1.73 m2
• 124 - 160 mL/min/1.73 m2 [older pediatric patients]

Because tazobactam is cleared by the kidneys and is a substrate of the transporters OAT1 and OAT3, inhibitors of these transporters should be avoided to ensure efficacy. Dosage adjustments of piperacillin-tazobactam and ceftolozane-tazobactam must be made for patients with impaired renal clearance.

The mean clearance rate of tazobactam was found to be 48.3-83.6 mL/min in patients admitted to the intensive care unit who were given renal replacement therapy and receiving intravenous piperacillin-tazobactam.

The clearance of tazobactam is dependent on renal function, as determined by renal clearance.

Elimination Route

As with other penicillins, PIPRACIL is eliminated primarily by glomerular filtration and tubular secretion; it is excreted rapidly as unchanged drug in high concentrations in the urine. Because PIPRACIL is excreted by the biliary route as well as by the renal route, it can be used safely in appropriate dosage in patients with severely restricted kidney function.

Tazobactam and its metabolite are mainly eliminated by the kidneys with about 80% of the administered dose eliminated as unchanged drug. The remaining drug is excreted as a single metabolite.

Pregnancy & Breastfeeding use

Piperacillin & Tazobactam should only be used during pregnancy if clearly indicated. Piperacillin is excreted in low concentrations in breast milk. Women who are breast-feeding should be treated only if clearly indicated.

Contraindication

Hypersensitivity to Piperacillin or any of the beta-lactam antibiotics and to Tazobactam or any other beta-lactamase inhibitor.

Special Warning

Renal insufficiency in adults, elderly and children (over 40 kg):

• CrCl 20-80 ml/min: Total Dosage 13.5 gm/day & Divided doses 4.5 gm 8 hourly
• CrCl <20 ml/min: Total Dosage 9 gm/day & Divided doses 4.5 gm 12 hourly

For patients on hemodialysis, the maximum daily dose is Piperacillin & Tazobactam 9 gm. In addition, (because hemodialysis removes 30%-50% of Piperacillin in four hours) one additional dose of Piperacillin & Tazobactam 2.25 gm should be administered following each dialysis period.

Renal insufficiency in children aged 2-12 years (or body weight less than 40 kg):

• CrCl >40: No adjustment necessary
• CrCl 20-39: Recommended Dosage 90 mg/kg 8 hourly & Maximum Daily Dosage 13.5 gm/day
• CrCl <20: Recommended Dosage 90 mg/kg 12 hourly & Maximum Daily Dosage 9 gm/day

For children weighing <50 kg on hemodialysis the recommended dose is 45 mg/kg every eight hours. Each patient must be monitored closely for signs of drug toxicity. Drug dose and interval should be adjusted accordingly.

Acute Overdose

There have been post-marketing reports of overdose with Piperacillin/Tazobactam. The majority of those events experienced including nausea, vomiting, and diarrhoea have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

Storage Condition

When reconstituted with water for injections or saline, reconstituted solutions will remain stable for 24 hours at 25°C and for 48 hours at 4°C. From a microbiological point of view, once opened, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

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